12/15-Lipoxygenase regulates the inflammatory response to bacterial products in vivo.
The peritoneal macrophage (Mphi) is the site of greatest 12/15-lipoxygenase (12/15-LOX) expression in the mouse; however, its immunoregulatory role in this tissue has not been explored. Herein, we show that 12/15-LOX is expressed by 95% of resident peritoneal CD11b(high) cells, with the remaining 5% being 12/15-LOX(-). 12/15-LOX(+) cells are phenotypically defined by high F4/80, SR-A, and Siglec1 expression, and enhanced IL-10 and G-CSF generation. In contrast, 12/15-LOX(-) cells are a dendritic cell population. Resident peritoneal Mphi numbers were significantly increased in 12/15-LOX(-/-) mice, suggesting alterations in migratory trafficking or cell differentiation in vivo. In vitro, Mphi from 12/15-LOX(-/-) mice exhibit multiple abnormalities in the regulation of cytokine/growth factor production both basally and after stimulation with Staphylococcus epidermidis cell-free supernatant. Resident adherent cells from 12/15-LOX(-/-) mice generate more IL-1, IL-3, GM-CSF, and IL-17, but less CCL5/RANTES than do cells from wild-type mice, while Staphylococcus epidermidis cell-free supernatant-elicited 12/15-LOX(-/-) adherent cells release less IL-12p40, IL-12p70, and RANTES, but more GM-CSF. This indicates a selective effect of 12/15-LOX on peritoneal cell cytokine production. In acute sterile peritonitis, 12/15-LOX(+) cells and LOX products were cleared, then reappeared during the resolution phase. The peritoneal lavage of 12/15-LOX(-/-) mice showed elevated TGF-beta1, along with increased immigration of monocytes/Mphi, but decreases in several cytokines including RANTES/CCL5, MCP-1/CCL2, G-CSF, IL-12-p40, IL-17, and TNF-alpha. No changes in neutrophil or lymphocyte numbers were seen. In summary, endogenous 12/15-LOX defines the resident MPhi population and regulates both the recruitment of monocytes/Mphi and cytokine response to bacterial products in vivo.
Dioszeghy
Vincent
V
Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Rosas
Marcela
M
Maskrey
Benjamin H
BH
Colmont
Chantal
C
Topley
Nicholas
N
Chaitidis
Pavlos
P
Kühn
Hartmut
H
Jones
Simon A
SA
Taylor
Philip R
PR
O'Donnell
Valerie B
VB
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000096:biosynthesis / Q000502:physiology; D000208:Acute Disease; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D001093:Arachidonate 15-Lipoxygenase / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis / Q000502:physiology; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010538:Peritonitis / Q000201:enzymology* / Q000276:immunology / Q000382:microbiology*; D013203:Staphylococcal Infections / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D013212:Staphylococcus epidermidis / Q000276:immunology* / Q000378:metabolism
C475064:12-15-lipoxygenase; D016207:Cytokines; D006893:Hydroxyeicosatetraenoic Acids; D018836:Inflammation Mediators; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C027356:11-hydroxy-5,8,12,14-eicosatetraenoic acid; C047628:8-hydroxyeicosatetraenoic acid; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase